Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

Sean Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, Mehraveh Garjani, Valentina Medvedeva, Casey Dalton, Chyi Haw Yvette Wong, Navdeep S. Chandel, Gerald Dienel, Robert G. Kalb*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival. Methods: We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene. Results: We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. Conclusions: We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

Original languageEnglish (US)
Article number101468
JournalMolecular Metabolism
Volume60
DOIs
StatePublished - Jun 2022

Keywords

  • ATP
  • G6PDH
  • Glycolysis
  • Neuron
  • Redox

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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